Previously used vaccines against infectious diseases have generally fallen into four categories: (I) specific components from the etiologic agents, including intact antigens, fragments thereof, or synthetic analogs of naturally occurring antigens or epitopes; (II) antiidiotypic antibodies, (III) the whole killed etiologic agent, or (IV) an avirulent (attenuated) derivative of the etiologic agent as a live vaccine. Attenuated vaccines have the advantage of acting like the natural infection with regard to their effect on immunity. They multiply in the host and, if immunogenic, tend to stimulate longer-lasting antibody production, to induce a cell-mediated response, and to induce antibody production and resistance at the portal of entry.
It has been possible to develop avirulent strains by the introduction of mutations into potentially pathogenic strains of the organism, which result in a lowered capacity of the mutated organism to survive in the host. The principles of the use of attenuated organisms are illustrated by reference to the Salmonella system; however, the principles are broadly applicable.
The reasons why attention has been paid to the development of avirulent strains of Salmonella are two fold. [For examples of the development of avirulent strains see Bacon et al. (1951), Curtiss and Kelly (1987), Germanier and Furer (1975), and Hoiseth and Stocker (1981)]. First, there is cumulative evidence that live attenuated strains of Salmonella are more effective than killed or subunit vaccines in inducing a protective immune response against infection by different species of Salmonella in humans and animals. [Hoiseth and Stocker (1981); Ashcroft et al. (1987), Collins (1974); Collins et al. (1966); Mukkur et al. (1987); and Robertson et al. (1983)]. Second, members of the Salmonella family with invasive properties, for example, S. typhimurium and S. typhi, after oral ingestion, enter deep tissues by attaching to, invading, and proliferating in the cells of the gut-associated lymphoid tissue (GALT; Peyer's Patches). [For example, see Carter and Collins (1974)]. Avirulent derivatives of S. typhimurium have been used to deliver heterologous antigens to this site as a means of stimulating a secretory as well as cellular and humoral immune responses to those antigens. [Clements and El-Morshidy (1984); Curtiss et al. (1986); Curtiss, (1988a); Curtiss, (1988b); Formal et al (1981); and Maskell et al. (1987)].
Several different strategies have been utilized to render Salmonella avirulent. These include the use of auxotrophic mutants such as aroA [Hoiseth and Stocker (1981)], asd or thy [Curtiss et al (1986)], or those defective in purine biosynthesis [McFarland and Stocker (1987); O'Callaghan et al. (1988)], mutants altered in the utilization or synthesis of carbohydrates such as galE [Germanier and Furer 1975; Fukasawa and Nikaido (1959); Stevenson and Manning (1985)]; temperature sensitive mutants [Morris et al. (1985)]; and mutants altered in global gene expression such as cya crp [Curtiss and Kelly (1987)]. These mutants have been tested and utilized with different degrees of success dependent on the host, bacterial species, and route of immunization. [Clements and El-Morshidy (1984); Curtiss et al. (1988a); Curtiss et al. (1988b); O'Callaghan et al. (1988)].